Current research is targeted towards

• Understanding factors affecting formulation of polymeric nanoparticles and hydrogels
• Establishing the therapeutic efficacy of drugs in the developed dosage forms
• Reducing the toxicity and increasing the efficacy of existing drugs
• Establishing utility of potent drugs for alternative indications that are not realized by conventional formulations
• Establishing IVIVC for the developed dosage forms

Glimpse of the activity

Example 1: Nanoparticles for oral delivery of challenging molecules
Cyclosporine is a potent immunosuppressive agent that has been widely used for the prevention of graft rejection following organ transplantation such as kidney, liver, heart, lung and pancreas as well as in the treatment of various autoimmune disorders. However, the oral bioavailability of cyclosporine is low and highly variable. Apart from the low and variable oral bioavailability, cyclosporine is a critical dose drug with narrow therapeutic window and the commercial formulation exhibits dose dependent Nephrotoxicity. To overcome these hurdles, cyclosporine loaded PLGA nanoparticles were designed and its plasma concentration vs time profile was compared with Sandimmune Neoral®. The cyclosporine nanoparticles showed improved bioavailability (relative bioavailability of 119.19% as compared to Sandimmune Neoral®) and sustained release for 5 days (Fig.1).

Fig. 1. Comparative in vivo plasma concentration vs. time profiles of cyclosporine (15 mg/kg body weight of animal as a single dose) administered orally as Sandimmune Neoral® and cyclosporine loaded NP (All values reported are mean ± S.D., n=3).

Example 2: Making alternative therapies work better using nanoparticles through oral route
The discovery of the role of free radicals in cancer, cardiovascular diseases, diabetes, autoimmune diseases, neurodegenerative disorders and aging has opened up a new arena in healthcare which has resulted in an extensive search for antioxidants and their role as prophylactic and therapeutic agents. In spite of proven pharmacological actions in humans, antioxidants have failed to gain the status of main line drugs and instead, are only being used as nutritional supplements for prophylaxis or adjuvant therapy due to their poor physicochemical and biopharmaceutical properties leading to their low oral bioavailability from conventional dosage forms. One such potent but pharmaceutically challenging antioxidant is Coenzyme Q10 (CoQ10). Low oral bioavailability of CoQ10 due to its poor aqueous solubility and low mucosal permeability lead to the need to apply novel delivery strategies to this molecule. The investigation illustrates that routinely used nutritional supplements such as CoQ10, which are generally found to be safe but associated with biopharmaceutical hurdles, can be used as first line therapeutic agents for prophylaxis and therapy by overcoming the problems associated with its delivery (Fig. 2).



Fig. 2. Effect of different CoQ10 formulations on systolic and diastolic blood pressure on 15th day after surgery in Goldblatt hypertensive rats. Data represented as Mean ± SEM (n=5-7).Understanding nanotechnology.

Example 3: Effect of molecular weights on in vivo performance of PLGA nanoparticles
Estradiol loaded nanoparticles using PLGA of different molecular weights and copolymer compositions were prepared to have lowest effective dose of estradiol. In vivo data showed that with all the PLGA nanoparticulate formulations, same dose (1 mg estradiol/rat) produced detectable blood levels for 5-11 days, depending on the molecular weight, copolymer composition and resultant particle size, compared to 1 day profile shown by pure drug, indicating improved bioavailability and sustained release with estradiol nanoparticles (Fig.3).

Fig. 3. Comparative in vivo profiles of PLGA nanoparticles of different molecular weights and compositions on oral administration. Inserts show plasma concentration vs. time profiles of estradiol pure drug on (a) intravenous and (b) oral administration (n = 3).

Example 4: Hydrogels for the delivery of Insulin
A feasible approach was established for pulsatile delivery of insulin using biosensitive chitosan in situ gelling systems, which can be used to modulate insulin release in response to the changes in physiological glucose concentrations. Blank auto-gels, blank and insulin-loaded biosensitive gels were thoroughly characterized (Fig. 4). In vitro swelling and insulin release studies of blank biosensitive gels and insulin-loaded gels indicate that the system was responsive to the changing glucose concentrations and pulsatile insulin release pattern was observed. In vivo PGL and PIL indicated the glucose lowering ability of gel and insulin releasing capability in pulsatile manner. All the glucose reduction values in treated animals (insulin gel and s.c. insulin) were biologically and statistical significant (Fig.5).

Fig. 4. (A) Insulin-loaded biosensitive chitosan-GP sol at room temperature. (B) Insulin-loaded biosensitive chitosan-GP gel at 37°C. Vial titling method showing gelation point (time required to gel) where sol stops flowing when tilted at 45°.

Fig. 5. Plasma glucose levels of biosensitive hydrogels (loaded with insulin and balnk) and commercially available insulin (3 IU/kg s.c.) in STZ-induced diabetic rats. Values reported are mean7SEM (n = 5-7). Significant differences of the mean values were evaluated by Student's t-test. A P-value of 0.05 was considered significant. *Significant difference (P<0.05), **significant difference (P<0.01) and ***significant difference (P<0.01). (a) vs. blank gel; (b) vs. plain insulin formulation.